Health Care Costs of Adults Treated for Attention-Deficit/Hyperactivity Disorder Who Received Alternative Drug Therapies

BACKGROUND: Many therapies exist for treating adult attention-deficit/hyperactivity disorder (ADHD), also referred to as attention-deficit disorder (ADD), but there is no research regarding cost differences associated with initiating alternative ADD/ADHD drug therapies in adults. OBJECTIVES: To compare from the perspective of a large self-insured employer the risk-adjusted direct health care costs associated with 3 alternative drugtherapies for ADD in newly treated patients: extended-release methylphenidate(osmotic release oral system-MPH), mixed amphetamine salts extended release (MAS-XR), or atomoxetine. METHODS: We analyzed data from a US claims database of 5 million beneficiaries from 31 large self-insured employers (1999-2004). Analysis was restricted to adults aged 18 to 64 years with at least 1 diagnosis of ADD/ADHD (International Classification of Diseases, Ninth Revision, Clinical Modification[ICD-9-CM] codes 314.0x—attention deficit disorder; 314.00—attention deficit disorder without hyperactivity; or 314.01—attention-deficit disorder with hyperactivity) and at least 1 pharmacy claim for OROS-MPH, MAS-XR,or atomoxetine identified using National Drug Codes. In preliminary analysis,we calculated the duration of index ADHD drug therapy as time from index therapy initiation to a minimum 60-day gap. Because the median duration of index ADHD drug therapy was found to be approximately 90 days, the primary measures were total direct medical plus drug costs and medical-only costs computed over 6 months following therapy initiation. Adults were required to have continuous eligibility 6 months before and 6 months after their latest drug therapy initiation and no ADHD therapy during the previous 6 months.Cost was measured as the payment amount made by the health plan to the provider rather than billed charges, and it excluded patient copayments and deductibles. Medical costs included costs incurred for all-cause in patient and outpatient/other services. Costs were adjusted for inflation to 2004 U.S. dollars using the consumer price index for medical care. T tests were used for descriptive cost comparisons. Generalized linear models (GLMs) were used to compare costs of adults receiving alternative therapies, adjusting for demographic characteristics, substance abuse, depression, and the Charlson Comorbidity Index. RESULTS: Of the 4,569 patients who received 1 of these 3 drug therapies for ADHD, 31.8% received OROS-MPH for a median duration of 99 days of therapy, 34.0% received MAS-XR for a median 128 days, and 34.2% received atomoxetine for a median 86 days. In the 6-month follow-up period, the mean(standard deviation) total medical and drug costs were $2,008 ($3,231) for OROS-MPH, $2,169 ($4,828) for MAS-XR, and $2,540 ($4,269) for atomoxetine-treated adults. The GLM for patient characteristics suggested that6-month, risk-adjusted mean medical costs, excluding drug costs, for adults treated with OROS-MPH were $142 less (10.4%, $1,220 vs. $1,362) compared with MAS-XR (P=0.022) and $132 less (9.8%, $1,220 vs. $1,352) compared with atomoxetine (P=0.033); risk-adjusted mean medical costs were not significantly different between MAS-XR and atomoxetine. The GLM comparison of risk-adjusted total direct costs, including drug cost, was on average $156 less (8.0%, $1,782 vs. $1,938) for OROS-MPH compared with MAS-XR (P=0.017) and $226 less (11.3%, $1,782 vs. $2,008) compared with atomoxetine (P less than 0.001); the risk-adjusted total direct costs were not significantly different between MAS-XR and atomoxetine. Two high-cost outliers (greater than 99.96th percentile, 1 each for OROS-MPH and atomoxetine) accounted for $47 (30%) of the $156 cost difference between OROS-MPH andMAS-XR and $11 (5%) of the $226 cost difference between OROS-MPH and atomoxetine, and the medical diagnoses for the highest-cost claims for these 2 outlier patients were unrelated to ADHD. CONCLUSIONS: After adjusting for patient characteristics including substance abuse, depression, and the Charlson Comorbidity Index, adults treated withOROS-MPH had, on average, slightly lower medical and total medical and drug costs than those treated with MAS-XR or atomoxetine over the 6-month period after drug therapy initiation. Approximately 30% of the cost difference compared with MAS-XR was attributable to 1 high-cost outlier with medical diagnoses for the highest-cost claim that were unrelated to ADHD.


What this study adds
• Over the 6-month period after drug therapy initiation, adults with ADHD initiated on OROS-MPH had, on average, 8% lower risk-adjusted total medical and pharmaceutical costs than did those initiated on MAS-XR and 11% lower costs compared with atomoxetine. However, these differences were affected by 1 outlier case for each comparison with diagnoses, such as chronic kidney disease and acute myocardial infarction, that were unrelated to ADHD or to accidents.
• Previous studies have indicated that MPH is a cost-effective treatment for children with ADHD.
• Health care costs of alternative drug therapies in adults with ADHD have not been evaluated. Studies in adults have focused on the economic burden of ADHD associated with an increase in comorbidity rates, risk of accidents, and health care costs but have not provided information about the health care costs associated with initiating alternative ADHD treatments in adults with ADHD. ered ac hildhood condition; only recently has thereb een a heightened awareness among clinicians and researchers regarding ADHD in adulthood. 2,3 Childhood ADHD persists into adulthood in up to 60% of diagnosed cases. 4,5 The clinical features of ADHD-associated symptoms include poor concentration, general disorganization, tendency to leave projects incomplete, inattention, poor school/work performance, problems with time management, difficulty controlling temper, impulsivity,and being hyperfocused. [4][5][6][7] ADHD patients also have an increased prevalence of comorbid conditions such as asthma, anxiety,b ipolar disorder,d epression, drug or alcohol abuse, antisocial disorder,oroppositional disorder. 2,8,9 The potential societal costs of adult ADHD arec onsiderable. ADHD has been associated with an increased risk of accidents, which would have consequences regarding the use and cost of health cares ervices. 10 Productivity loss of adults with ADHD is estimated to be 35 days ay ear. 1 The estimated burden of ADHD in the United States was $31.6 billion in 2000, and 45% of that burden was attributable to excess health carec osts of family members of patients with ADHD. 11 Compared with am atched cohort, ADHD patients had almost 3t imes greater annual health carec osts, and family members had approximately 1.9 times higher annual health caree xpenditures compared with am atched cohort of family members of non-ADHD patients. 12 ADHD in adults is amenable to treatment and is best controlled by ac ombination of medications and psychosocial interventions. 6,13,14 Common medications used for the treatment of ADHD in adults arestimulants (e.g., methylphenidate [MPH], mixed amphetamine salts [MAS], dextroamphetamine) or nonstimulants (e.g., atomoxetine). 4,8,[15][16][17] In the past, treatment options usually included either short-or intermediate-acting stimulants and antidepressants. 18 Recently,s timulant products have entered the marketplace in extended-release formulations; the first methylphenidate product that lasts 12 hours with once-daily dosing is osmotic release oral system (OROS)-MPH, and the once-daily amphetamine preparation is MAS-XR. Atomoxetine hydrochloride is the first nonstimulant to receive an indication for ADHD in adults from the U.S. Food and Drug Administration. 15 Both stimulant and nonstimulant treatments have been shown to be effective in improving ADHD symptoms. 17,19 Stimulant therapy led to improvement in 65% to 75% versus 5% to 30% of patients randomized to placebo. 19 Nonstimulant therapy has also been shown to improve symptoms assessed with the ADHD rating scales. 17 Quantifying costs related to ADHD and to alternative therapies is important in order to understand the economic impact of the condition and provide abasis for the development of programs and policies to assist patients suffering from this disability.T he objective of this article is to comparer iskadjusted medical and total health carecosts of adults diagnosed with ADHD initiated on extended-release methylphenidate (OROS-MPH, Concerta), mixed amphetamine salts extended release (MAS-XR, Adderall XR), or atomoxetine (Strattera) from the perspective of alarge self-insured employer.
nn Methods

Data
Our study is based on data from ad eidentified administrative claims database maintained by Ingenix, Inc. (Eden Prairie, MN) containing medical and demographic information on privately insured employees, retirees, and their spouses and dependents from 31 large self-insured companies in the United States. The claims cover services provided from January1999 through December 2004. The 31 companies have national operations, span ab road array of industries and occupations, and cover approximately 5m illion beneficiaries. On average, each employer has 2t o3h ealth plans. The database includes medical and pharmacy claims for all employees plus their spouses and dependents. Data on the monthly eligibility of beneficiaries area vailable, as well as employee demographic information such as age, gender,geographic region of residence, and employee status of the primaryb eneficiary. The formulary status of ADHD drug therapies for these health plans is not known.

Sample Selection
The study sample was drawn from all 31 companies and included adults between the ages of 18 and 64 years during the study period. Patients wereincluded in the ADHD sample if they met the following criteria (outlined in the Figure):

Cost Estimation
Cost analyses werec onducted from the third-party payer' sp erspective (i.e., costs wered efined as payments to providers by third-party payers after subtraction of all member cost share including deductibles, coinsurance, and copayments). All costs werem easured on a6 -month basis and adjusted for inflation to 2004 U.S. dollars using the consumer price index for medical care. The decision to estimate 6-month costs was based on preliminarya nalysis of the duration of therapy.D uration of therapy was defined as the time from index therapy initiation to am inimum 60-day gap in the index therapy supply.I nt he preliminaryanalysis, the overall median duration of index drug therapy was approximately 90 days.
Medical costs werecalculated based on reimbursements from the employer to health careproviders for inpatient care, hospital outpatient care(e.g., outpatient surgery), physician services, and emergency room visits, as well as other ancillarys ervices (e.g., physical therapy,l aboratorys ervices). Costs werec ategorized in 2m utually exclusive categories, inpatient services and outpatient/other services, based on the place of service code associated with each claim. We relied on place of service categories because revenue codes werenot available in the data. Costs of inpatient services wered efined using claims with ap lace of service specified as hospital inpatient, rehabilitation center, residential treatment center,o rp sychiatric facility.A ll other medical costs weregrouped into an "outpatient and other costs" categoryt hat also included services with place of service specified as emergency treatment centers or hospital emergency rooms. Number of outpatient/other visits was defined as the summed number of unique days with ac laim with place of service other than hospital inpatient, rehabilitation center, residential treatment center,o rp sychiatric facility.T otal health carecosts weredefined as medical (inpatient and outpatient) plus prescription drug costs.
Costs attributable to psychotherapy,as ubset of medical costs, werealso reported. Psychotherapy encounters could have occurred in either an inpatient or outpatient setting, and we did not attempt to divide them into inpatient and outpatient subcategories. Psychotherapy costs weree stimated using medical claims with Current Procedural Terminology (CPT) codes for psychotherapy (CPT codes 90804-90857, 96150-96155). Psychotherapy visits weredefined as the summed number of unique days with at least 1psychotherapy claim.
For each claim with an inpatient place of service, we identified the reason for the hospital use based on up to 2primaryor secondarydiagnosis codes. The most frequently recorded diagnoses wered esignated as the reason for hospital services, irrespective of whether they appeared as primaryo rs econdary on the claim.
About 0.1% of the medical claims had am issing amount paid. Aproceduredescribed as stratified hot-deck imputations, outlined by Little and Rubin, was applied to impute the missing paid amounts from randomly selected claims with complete paid amounts that contained the same procedurecode, place of service, and type of service. 20

Analyses
All analyses werep erformed on an intent-to-treat basis (i.e., adults weregrouped by their index therapy). Statistical significance was evaluated at the 0.05 significance level. The proportions of patients with at least 1inpatient place of service claim, emergency room claim (defined as aclaim with aplace of service in an emergency treatment center or hospital emergency room), and outpatient or other claim over the 6-month follow-up period werecompared between OROS-MPH and MAS-XR and between

Sample Selection (Population of Approximately 5Million Beneficiaries)
OROS-MPH and atomoxetine using chi-squaretests. Six-month medical (inpatient and outpatient) and drug costs werec alculated for adults treated with OROS-MPH, MAS-XR, or atomoxetine. T tests wereu sed for ad escriptive comparison of observed costs among the treatment groups. Multivariate regression models wereu sed to compare medical and direct health carec osts between OROS-MPH and each of the other 2therapies while adjusting for baseline patient characteristics.
Ag eneralized linear model (GLM) specification with al og link function and gamma distribution for the error term was used to resolve the issue of askewed cost distribution common in claims data analysis. 21 In contrast with the traditional logordinaryl east squares regression, GLM provides morer obust coefficient estimates. 22 Also, the log link function of the mean response enables coefficients to be directly back-transformed into the original dollar scale and avoids the issue of potentially biased estimates that may result from using the Duan smearing estimation method. 23 Patient characteristics included age, gender,r egion, selected comorbidities (substance abuse and depression/anxiety), and the Charlson Comorbidity Index. Primarya nd secondaryd iagnoses during the 6m onths prior to initiation of index therapy wereu sed to identify the selected comorbidities and construct the Charlson Comorbidity Index. Substance abuse was defined as adiagnosis with 1ofthe following ICD-9-CM codes: V65.42, 305.xx, 304.xx, 292.xx, 303.xx, 305.0x, or 291.xx. Depression/anxiety was defined as ad iagnosis with ICD-9-CM codes 296.xx, V79.0x, 311.xx, or 300.0x. We chose to adjust for depression/anxiety and substance abuse based on prior studies reporting that patients diagnosed with ADHD werem orel ikely to have anxiety,b ipolar disorder,d epression, drug or alcohol abuse, or conduct disorders compared with matched controls. 9 Depression was found to be the most common comorbid condition among patients with ADHD. 24 Another study reported that patients weremorelikely to receive atomoxetine compared with stimulants if they had aprior historyofbipolar disorder,anxiety, substance abuse, or antidepressant use. 25 The Charlson Comorbidity Index is aw eighted sum of 17 comorbidities in which comorbidity weights areb ased on adjusted risk of 1-year mortality; the higher the Charlson Comorbidity Index, the higher the illness burden. 26 ICD-9-CM diagnosis codes defined by Romano et al. wereused to identify the included comorbidities: myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, dementia, chronic pulmonaryd isease, rheumatologic disease, peptic ulcer disease, mild liver disease, moderate to severel iver disease, mild to moderate diabetes, diabetes with complications, hemiplegia or paraplegia, renal disease, any malignancy including lymphoma or leukemia, metastatic solid tumor,a nd AIDS. 27 All analyses werep erformed using SAS Version 9.1 (SAS Institute, Cary, NC).
nn Results

Demographics: 6-Month Preperiod
Adults with ad iagnosis of attention-deficit disorder (ADD)/ ADHD receiving OROS-MPH, MAS-XR, or atomoxetine were, on average, 32 years old. Approximately 43% of the adults in the study sample weref emale, 3% had ad iagnosis related to substance abuse in the previous 6m onths, and 26% had a depression/anxiety-related diagnosis in the previous 6m onths (Table 1).
By using the criteria of medical cost in excess of $50,000 or approximately the 99.96th percentile, 2patients weremedical cost outliers. One patient treated with MAS-XR had total medical and pharmacy costs of $136,300, of which $134,712 werem edical costs; the highest cost claim for this patient was associated with diagnosis codes for chronic kidney disease (ICD-9-CM code 585.xx) and iron deficiency anemia (ICD-9-CM code 280.9x). One patient who received atomoxetine had total medical and pharmacy costs of $58,554, of which $55,950 werem edical costs; the highest cost claim was associated with diagnosis codes for acute myocardial infarction (ICD-9-CM code 410.21) and paroxysmal ventricular tachycardia (ICD-9-CM code 427.1).

Multivariate Regression
The GLM comparison of health carec osts in the 6m onths after therapy initiation (adjusting for potential confounders, Table 3) found that risk-adjusted direct health carec osts of OROS-MPH-treated adults wereo na verage $156 (8.0%) less than those of MAS-XR-treated adults ( P =0.017) and $226 (11.3%) less than those of atomoxetine-treated adults ( P =0.001). The health carec ost difference was primarily due to differences in medical costs; average medical costs for OROS-MPH-treated adults were$ 142 (10.4%) less than those of MAS-XR-treated adults ( P =0.022) and $132 (9.8%) less than those of atomoxetine-treated adults ( P =0.033). nn

Discussion
Our analysis of aprivately insured claims database indicates that over the 6-month period following therapy initiation, adults treated with OROS-MPH had, on average, lower all-cause medical and total health carec osts than those treated with MAS-XR or atomoxetine after adjusting for patient characteristics. To our knowledge, this is the first study comparing all-cause health carecosts of adults diagnosed with ADHD and receiving alternative ADHD drug therapies. 28 Previous studies have indicated that MPH is ac ost-effective treatment for children with ADHD. [29][30][31] Astudy by Marchetti et al. developed adecision-analytic model to estimate the total expected costs for the treatment and management of school-age children with ADHD using 6c ommonly prescribed pharmacotherapies: methylphenidate immediate release/extended release (MPH-IR/ER), methylphenidate immediate release (MPH-IR), branded MPH-IR/ER (Metadate CD), OROS-MPH (Concerta), branded MPH-IR (Ritalin), and ac ombination of dextroamphetamine and amphetamine salts (Adderal). 32 This study found that dextroamphetamine and amphetamine salts had the highest total expected costs among the ADHD pharmacotherapies evaluated: the average total annual expected cost in 2001 U.S. dollars per treated patient was $1,710 for Metadate CD, $1,876 for Concerta, $2,061 for MPH-IR/ER, $2,122 for MPH-IR, $2,392 for Ritalin, and $2,567 for Adderall.
Other published studies have focused on the direct health carec osts of adults with ADHD but did not provide cost comparisons of adults with ADHD on different drug therapies. [9][10][11] Those studies compared the costs of carefor adults with ADHD with the costs in matched controls and concluded that ADHD is associated with significant economic burden. Compared with the control group, adults diagnosed with ADHD weres ignifi-Health Care Costs of Adults Treated for Attention-Deficit/Hyperactivity Disorder Who Received Alternative Drug Therapies cantly morel ikely to have ac omorbid diagnosis of asthma, anxiety,b ipolar disorder,d epression, drug or alcohol abuse, antisocial disorder,oroppositional disorder (e.g., 4.7% vs. 2.9% for asthma and 4.5% vs. 0.58% for bipolar disorder). 9 Adjusting for patient characteristics, adults with ADHD had an excess medical cost of $2,880 ( P <0.001). 9 Costs associated with accident claims aremorethan 3times higher in adults with ADHD than in controls. 10 The total excess cost of ADHD in the United States in 2000 was $31.6 billion, including the higher costs associated with family members of persons with ADHD. 11 A recently published paper also reported national estimates and characteristics of ambulatoryvisits by adults with ADHD in the United States but did not comparethe cost of alternative ADHD drug treatments. 33 Our study assessed the real-world drug and total medical costs associated with initiation of 3a lternative drug therapies for adult patients with adiagnosis of ADHD.

Limitations
Foremost among the limitations of our study was its short duration. The overall median length of index ADHD drug therapy was approximately 90 days, ranging from am edian of 86 days for atomoxetine to 99 days for OROS-MPH to 128 days for MAS-XR. We anticipated this relatively short therapy period based on ap revious study by Perwien et al., which concluded that even though ADHD patients continued their ADHD medication for several months, they did not consistently take medication for morethan 2months. 24 Second, our study did not directly assess the clinical severity of ADHD. Like all administrative claims data-bases, ADHD severity could not be determined from the data that we accessed. To assess and control for subjects' physical conditions, we used acommon proxy of comorbidity risk measurement, the Charlson Comorbidity Index, and selected comorbidities. 5,9,11 However,o ther risk-adjustment alternatives to the Charlson Comorbidity Index also exist. 34,35 Studies have found similar mortality predictive accuracy with the Romano-Charlson Comorbidity Index (used in our analysis) and the Elixhauser comorbidities. 36,37 Third, we did not restrict ICD-9-CM codes specifically to ADHD. We included ICD-9-CM codes 314.00 (attentiondeficit disorder without hyperactivity,a lso known as ADD of predominantly the inattentive type 38 )a nd 314.0 (nonspecific attention-deficit disorder) as well as 314.01, which is specific to attention-deficit disorder with hyperactivity (ADHD). While other researchers have used ICD-9-CM codes 314.0x to describe ADHD, 24,25 the correct definition of code 314.0x is ADD because ICD-9-CM code 314.00 is intended to specify ADD without hyperactivity.A si st rue of much of the research in this area, we did not analyze the data with respect to the use of ICD-9-CM code 314.00 versus 314.01.
Fourth, we did not requireh ealth careo rh ospital costs to be related to ADD/ADHD; hence, we report all-cause health carea nd hospital costs. While ADD/ADHD (ICD-9-CM code 314.0x) was 1o ft he 3m ost common primaryo rs econdary reasons for hospital inpatient service use, we did not exclude any hospital service use during the follow-up period. The other 2most common principal reasons for inpatient service use wereM DD (ICD-9-CM codes 296.2x and 296.3x) and depres- sive disorder (ICD-9-CM code 311.xx). As ignificantly higher proportion of atomoxetine patients had inpatient services during the follow-up period, and the average inpatient service costs for OROS-MPH werel ower compared with MAS-XR and atomoxetine. Calculating the cost of only claims with an ADHD diagnosis, psychotherapy visits, and ADHD medications is likely to underestimate ADHD-related costs considering that research has shown that ADHD is associated with an increased risk of accidents. 10 Another study has demonstrated that only asmall percentage of total health carecosts wereclearly disorder specific. The authors concluded that either calculating the costs of medical services used in disease management underestimates the full economic impact of the disorder or that the relationship between the disorder and total health carecost was not causal. 39 We did not use this method of aggregating and reporting disease-specific versus other-cause utilization and costs, which may have helped to better inform the discussion about ADD/ADHD-related costs and costs that arenot directly attributable to ADD/ADHD.
Fifth, the inclusion of 2p atients with outlier medical costs, defined as $50,000 or moreper patient, was partly responsible for the differences in mean costs observed in the descriptive analysis. For example, 1p atient in the MAS-XR group had medical costs of $134,712 and total medical and pharmacy costs of $136,300, which was approximately $95,924 more than the highest-cost outlier for OROS-MPH ($35,597 in medical costs, $40,776 in total medical and pharmacy costs) or approximately $77,746 moret hanthe a tomoxetine patient ($55,950 in medical costs, $58,554 in total medical and pharmacy costs (see Table 2). Differences in median 6-month total health carecosts, which arenot as sensitive as the means to outliers, ranged from $12 to $209. However,o ur multivariate analysis adjusted for the skewness that is typical of cost data, controlling for demographic characteristics, substance abuse, depression, and the Charlson Comorbidity Index.
Sixth, the categorization of inpatient services and outpatient/ other services relied on place-of-service codes. To the extent that some emergency room and outpatient visits werec oded with a place of service designated as hospital inpatient, rehabilitation center,r esidential treatment center,o rp sychiatric facility,t heir costs werecategorized into inpatient services costs. However,inpatient service and outpatient/other service costs weremutually exclusive categories; therefore, our conclusions based on medical and total health carecosts remain valid.
Seventh, potential selection bias cannot be fully adjusted. Even though we adjusted for patient baseline characteristics, Charlson comorbidity index, and selected comorbidities, 5,9,11 those adjustments wereb ased on diagnoses provided in the 6m onths prior to therapy initiation. Therefore, potential baseline differences among the 3g roups may not be fully adjusted due to the limited information available.
Eighth, caremust be taken in generalizing the results of this study because the sample is not representative of the entireU.S. population. Our data did not include low-income, Medicaid, and Medicarep opulations. In addition, the cost (i.e., provider payment) measurement did not include patient deductible or coinsurance amounts, nor did it reflect provider-submitted charges.
Ninth, we do not know the formularystatus of these drugs. If one drug was morel ikely to be an onformularyd rug with a higher copayment, the use of net payer cost after subtraction of member cost sharecould introduce asystematic bias that would show lower plan cost for the nonformularydrug.
Last, it is possible that mental illness in general and ADHD specifically may be underreported in claims data due to social stigma, practice differences between primaryc arep hysicians and specialists, and other factors. The purpose of our study is to comparet he costs associated with alternative ADHD drug therapy for patients receiving ad iagnosis of ADHD. There appears to be no reason to believe that this potential problem concerning the underreporting of ADHD in medical claims would be distributed disproportionately among our 3drug treatment groups. Further studies might be conducted to assess the cost implications of the possible under-reporting of ADHD.

nn Conclusions
Over the 6-month period following drug therapy initiation, adults with adiagnosis of ADHD initiated on OROS-MPH had, on average, 8% lower total all-cause drug and medical costs compared with MAS-XR or 11% lower total costs compared with atomoxetine. Further research is needed to evaluate clinical and economic outcomes in adults diagnosed with ADHD who arereceiving alternative therapies.